Journal of Hepatology
Volume 48 , Pages S2-S19 , 2008

Hepatitis B: Reflections on the current approach to antiviral therapy

  • Fabien Zoulim

      Affiliations

    • INSERM, U871, 69003 Lyon, France
    • Université Lyon 1, IFR62 Lyon-Est, 69008 Lyon, France
    • Hospices Civils de Lyon, Hôtel Dieu, Liver Unit, 69002 Lyon, France
  • ,
  • Robert Perrillo

      Affiliations

    • Hepatology Division, Baylor University Medical Center, 3500 Gaston Avenue, Dallas, TX 75206, USA
    • Corresponding Author InformationCorresponding author.

References 

  1. Lavanchy D. Hepatitis B virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures. J Viral Hepat. 2004;11:97–107
  2. WHO. Hepatitis B vaccines. Wkly Epidemiol Rec 2004;79:255–263.
  3. Fattovich G. Natural history of hepatitis B. J Hepatol. 2003;39:S50–S58
  4. Perrillo RP. Acute flares in chronic hepatitis B: the natural and unnatural history of an immunologically mediated liver disease. Gastroenterology. 2001;120:1009–1022
  5. Rehermann B. Immune responses in hepatitis B virus infection. Semin Liver Dis. 2003;23:21–38
  6. Perrillo RP, Lai CL, Liaw YF, Dienstag JL, Schiff ER, Schalm SW, et al. Predictors of HBeAg loss after lamivudine treatment for chronic hepatitis B. Hepatology. 2002;36:186–194
  7. Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology. 2007;45:507–539
  8. de Franchis R, Hadengue A, Lau G, Lavanchy D, Lok A, McIntyre N, et al. EASL International Consensus Conference on Hepatitis B. 13–14 September, 2002 Geneva, Switzerland. Consensus statement (long version). J Hepatol 2003;39:S3–S25.
  9. Liaw YF, Leung N, Guan R, Lau GK, Merican I, McCaughan G, et al. Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2005 update. Liver Int 2005;25:472–489.
  10. Chu CJ, Hussain M, Lok AS. Quantitative serum HBV DNA levels during different stages of chronic hepatitis B infection. Hepatology. 2002;36:1408–1415
  11. Manesis EK, Papatheodoridis GV, Sevastianos V, Cholongitas E, Papaioannou C, Hadziyannis SJ. Significance of hepatitis B viremia levels determined by a quantitative polymerase chain reaction assay in patients with hepatitis B e antigen-negative chronic hepatitis B virus infection. Am J Gastroenterol. 2003;98:2261–2267
  12. Papatheodoridis G, Manesis E, Manolakopoulos S, Goulis J, Chrysanthos N, Bilalis A, et al. HBeAg-negative chronic hepatitis B (CHBe−) in chronic HBV patients with serum HBV-DNA levels below 2000IU/mL. J Hepatol. 2007;46:S183
  13. Bonino F, Brunetto MR. Chronic hepatitis B e antigen (HBeAg) negative, anti-HBe positive hepatitis B: an overview. J Hepatol. 2003;39:S160–S163
  14. Piton A, Poynard T, Imbert-Bismut F, Khalil L, Delattre J, Pelissier E, et al. Factors associated with serum alanine transaminase activity in healthy subjects: consequences for the definition of normal values, for selection of blood donors, and for patients with chronic hepatitis C. MULTIVIRC Group. Hepatology. 1998;27:1213–1219
  15. Kim HC, Nam CM, Jee SH, Han KH, Oh DK, Suh I. Normal serum aminotransferase concentration and risk of mortality from liver diseases: prospective cohort study. BMJ. 2004;328:983
  16. Yang L, Xu K, Zhao Y, Wu Z, Chen T, Qin Z, et al. Clinical significance of liver biopsy in chronic hepatitis B patients with persistently normal transaminase. Chin J Dig Dis. 2002;3:150–153
  17. Mohamadnejad M, Montazeri G, Fazlollahi A, Zamani F, Nasiri J, Nobakht H, et al. Noninvasive markers of liver fibrosis and inflammation in chronic hepatitis B-virus related liver disease. Am J Gastroenterol. 2006;101:2537–2545
  18. Yuen MF, Yuan HJ, Wong DK, Yuen JC, Wong WM, Chan AO, et al. Prognostic determinants for chronic hepatitis B in Asians: therapeutic implications. Gut. 2005;54:1610–1614
  19. Lai CL, Yuen MF. The natural history and treatment of chronic hepatitis B: a critical evaluation of standard treatment criteria and end points. Ann Intern Med. 2007;147:58–61
  20. Keeffe EB, Dieterich DT, Han SH, Jacobson IM, Martin P, Schiff ER, et al. A treatment algorithm for the management of chronic hepatitis B virus infection in the United States: an update. Clin Gastroenterol Hepatol. 2006;4:936–962
  21. Perrillo RP, Gish RG, Peters M, Keeffe EB, Alberti A, Buti M, et al. Chronic hepatitis B: a critical appraisal of current approaches to therapy. Clin Gastroenterol Hepatol. 2006;4:233–248
  22. Yang HI, Lu SN, Liaw YF, You SL, Sun CA, Wang LY, et al. Hepatitis B e antigen and the risk of hepatocellular carcinoma. N Engl J Med. 2002;347:168–174
  23. Iloeje UH, Yang HI, Su J, Jen CL, You SL, Chen CJ. Predicting cirrhosis risk based on the level of circulating hepatitis B viral load. Gastroenterology. 2006;130:678–686
  24. Yu MW, Yeh SH, Chen PJ, Liaw YF, Lin CL, Liu CJ, et al. Hepatitis B virus genotype and DNA level and hepatocellular carcinoma: a prospective study in men. J Natl Cancer Inst. 2005;97:265–272
  25. Chen G, Shen FM, Iloeje UH, Evans A. Viral load as a predictor of liver disease in chronic hepatitis B infection. Hepatology. 2004;40:594A
  26. Iloeje U, Yang H, Su J, Jen C, Kuo E, You S, et al. Viral load is a strong predictor of hepatocellular carcinoma risk in people chronically infected with hepatitis B virus and normal serum alanine aminotransferase level. J Hepatol. 2005;42:179
  27. Evans A, Fabre R, Chen G, Pasternak L, Iloeje U, London W. Hepatitis B viral load is associated with the development of hepatocellular carcinoma. Hepatology. 2004;40:602A
  28. Chen G, Lin W, Shen F, Iloeje U, London W, Evans A. Viral load as a predictor of mortality from hepatocellular carcinoma and chronic liver disease in chronic hepatitis B infection. J Hepatol. 2005;42:173
  29. Chen CJ, Yang HI, Su J, Jen CL, You SL, Lu SN, et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA. 2006;295:65–73
  30. Perrillo R. Hepatitis B virus replication×time equals trouble. Gastroenterology. 2006;130:989–991
  31. Liaw YF, Sung JJ, Chow WC, Farrell G, Lee CZ, Yuen H, et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med. 2004;351:1521–1531
  32. Sherman M. Predicting survival in hepatitis B. Gut. 2005;54:1521–1523
  33. Hui CK, Leung N, Yuen ST, Zhang HY, Leung KW, Lu L, et al. Natural history and disease progression in Chinese chronic hepatitis B patients in immune-tolerant phase. Hepatology. 2007;46:395–401
  34. Lin CL, Liao LY, Liu CJ, Yu MW, Chen PJ, Lai MY, et al. Hepatitis B viral factors in HBeAg-negative carriers with persistently normal serum alanine aminotransferase levels. Hepatology. 2007;45:1193–1198
  35. Prati D, Taioli E, Zanella A, Della Torre E, Butelli S, Del Vecchio E, et al. Updated definitions of healthy ranges for serum alanine aminotransferase levels. Ann Intern Med. 2002;137:1–10
  36. Rang A, Bruns M, Heise T, Will H. Antiviral activity of interferon-alpha against hepatitis B virus can be studied in non-hepatic cells and is independent of MxA. J Biol Chem. 2002;277:7645–7647
  37. Peters M, Walling DM, Waggoner J, Avigan MI, Sjogren M, Hoofnagle JH. Immune effects of alpha-interferon in chronic liver disease. J Hepatol. 1986;3:S283–S289
  38. Perrillo RP, Schiff ER, Davis GL, Bodenheimer HC, Lindsay K, Payne J, et al. A randomized, controlled trial of interferon alfa-2b alone and after prednisone withdrawal for the treatment of chronic hepatitis B. The Hepatitis Interventional Therapy Group. N Engl J Med. 1990;323:295–301
  39. Cooksley WG, Piratvisuth T, Lee SD, Mahachai V, Chao YC, Tanwandee T, et al. Peginterferon alpha-2a (40kDa): an advance in the treatment of hepatitis B e antigen-positive chronic hepatitis B. J Viral Hepat. 2003;10:298–305
  40. Janssen HL, van Zonneveld M, Senturk H, Zeuzem S, Akarca US, Cakaloglu Y, et al. Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial. Lancet. 2005;365:123–129
  41. Lau GK, Piratvisuth T, Luo KX, Marcellin P, Thongsawat S, Cooksley G, et al. Peginterferon alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B. N Engl J Med. 2005;352:2682–2695
  42. Marcellin P, Lau GK, Bonino F, Farci P, Hadziyannis S, Jin R, et al. Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B. N Engl J Med. 2004;351:1206–1217
  43. Nair S, Perrillo RP. Serum alanine aminotransferase flares during interferon treatment of chronic hepatitis B: is sustained clearance of HBV DNA dependent on levels of pretreatment viremia?. Hepatology. 2001;34:1021–1026
  44. Flink HJ, Sprengers D, Hansen BE, van Zonneveld M, de Man RA, Schalm SW, et al. Flares in chronic hepatitis B patients induced by the host or the virus? Relation to treatment response during peg-interferon {alpha}-2b therapy. Gut. 2005;54:1604–1609
  45. van Zonneveld M, Honkoop P, Hansen BE, Niesters HG, Murad SD, de Man RA, et al. Long-term follow-up of alpha-interferon treatment of patients with chronic hepatitis B. Hepatology. 2004;39:804–810
  46. Lau DT, Everhart J, Kleiner DE, Park Y, Vergalla J, Schmid P, et al. Long-term follow-up of patients with chronic hepatitis B treated with interferon alfa. Gastroenterology. 1997;113:1660–1667
  47. Flink HJ, van Zonneveld M, Hansen BE, de Man RA, Schalm SW, Janssen HL. Treatment with Peg-interferon alpha-2b for HBeAg-positive chronic hepatitis B: HBsAg loss is associated with HBV genotype. Am J Gastroenterol. 2006;101:297–303
  48. Piratvisuth T, Luo K-X, Marcellin P, Chang W-Y, Berg T, Flisiak R, et al. Effect of ALT flares on efficacy and safety of peginterferon α-2a (40kDa) (Pegasys®), peginterferon α-2a plus lamivudine and lamivudine in HBeAg-positive chronic hepatitis B. J Hepatol. 2005;42:189
  49. Cooksley G, Manns M, Lau G, Liaw Y, Marcellin P, Chow W, et al. Effect of genotype and other baseline factors on response to peginterferon α-2a (40kDa) (Pegasys®) in HBeAg-positive chronic hepatitis B: Results from a large, randomized study. J Hepatol. 2005;42:31
  50. Bonino F, Marcellin P, Lau GK, Hadziyannis S, Jin R, Piratvisuth T, et al. Predicting response to peginterferon alpha-2a, lamivudine and the two combined for HBeAg-negative chronic hepatitis B. Gut. 2007;56:699–705
  51. Marcellin P, Bonino F, Lau G, Farci P, Yurdaydin C, Piratvisuth T, et al. Virological and biochemical response in patients with HBeAg-negative CHB treated with peginterferon α-2a (40kDa) ± lamivudine: 3-year follow-up results. J Hepatol. 2007;46:S25
  52. Chan HL, Hui AY, Wong VW, Chim AM, Wong ML, Sung JJ. Long-term follow-up of peginterferon and lamivudine combination treatment in HBeAg-positive chronic hepatitis B. Hepatology. 2005;41:1357–1364
  53. Chan HL, Leung NW, Hui AY, Wong VW, Liew CT, Chim AM, et al. A randomized, controlled trial of combination therapy for chronic hepatitis B: comparing pegylated interferon-alpha2b and lamivudine with lamivudine alone. Ann Intern Med. 2005;142:240–250
  54. Lutgethetmann M, Wursthorn K, Buggisch P, Zollner B, Zankel M, Fischer C, et al. 48 weeks of adefovir mono therapy following 48 weeks of combination therapy with peginterferon alpha-2b and adefovir leads to additional biochemical and virological improvement. J Hepatol. 2007;44:S189
  55. Wursthorn K, Lutgehetmann M, Dandri M, Volz T, Buggisch P, Zollner B, et al. Peginterferon alpha-2b plus adefovir induce strong cccDNA decline and HBsAg reduction in patients with chronic hepatitis B. Hepatology. 2006;44:675–684
  56. Sarin SK, Sood A, Kumar M, Arora A, Amrapurkar D, Sharma BC, et al. Effect of lowering HBV DNA levels by initial antiviral therapy before adding immunomodulator on treatment of chronic hepatitis B. Am J Gastroenterol. 2007;102:96–104
  57. Manesis EK, Hadziyannis SJ. Interferon alpha treatment and retreatment of hepatitis B e antigen-negative chronic hepatitis B. Gastroenterology. 2001;121:101–109
  58. Lampertico P, Del Ninno E, Vigano M, Romeo R, Donato MF, Sablon E, et al. Long-term suppression of hepatitis B e antigen-negative chronic hepatitis B by 24-month interferon therapy. Hepatology. 2003;37:756–763
  59. Manesis E, Hadziyannis S, Agelopoulou O, Hadziyannis S. HBsAg levels under interferon and lamivudine therapy in HBeAg-negative chronic hepatitis B (CHBe−) patients. J Hepatol. 2005;42:185
  60. Gish RG, Lau DT, Schmid P, Perrillo R. A pilot study of extended duration peginterferon alfa-2a for patients with hepatitis B e antigen-negative chronic hepatitis B. Am J Gastroenterol. 2007;102:2718–2723
  61. Buster EH, Janssen HL. Antiviral treatment for chronic hepatitis B virus infection – immune modulation or viral suppression?. Neth J Med. 2006;64:175–185
  62. Perrillo RP. Therapy of hepatitis B – viral suppression or eradication?. Hepatology. 2006;43:S182–S193
  63. Zoulim F. Mechanism of viral persistence and resistance to nucleoside and nucleotide analogs in chronic hepatitis B virus infection. Antiviral Res. 2004;64:1–15
  64. Seigneres B, Pichoud C, Martin P, Furman P, Trepo C, Zoulim F. Inhibitory activity of dioxolane purine analogs on wild-type and lamivudine-resistant mutants of hepadnaviruses. Hepatology. 2002;36:710–722
  65. Zoulim F, Dannaoui E, Borel C, Hantz O, Lin TS, Liu SH, et al. 2′,3′-Dideoxy-beta-l-5-fluorocytidine inhibits duck hepatitis B virus reverse transcription and suppresses viral DNA synthesis in hepatocytes, both in vitro and in vivo. Antimicrob Agents Chemother. 1996;40:448–453
  66. Delaney WEt, Ray AS, Yang H, Qi X, Xiong S, Zhu Y, et al. Intracellular metabolism and in vitro activity of tenofovir against hepatitis B virus. Antimicrob Agents Chemother. 2006;50:2471–2477
  67. Seigneres B, Aguesse-Germon S, Pichoud C, Vuillermoz I, Jamard C, Trepo C, et al. Duck hepatitis B virus polymerase gene mutants associated with resistance to lamivudine have a decreased replication capacity in vitro and in vivo. J Hepatol. 2001;34:114–122
  68. Seifer M, Hamatake RK, Colonno RJ, Standring DN. In vitro inhibition of hepadnavirus polymerases by the triphosphates of BMS-200475 and lobucavir. Antimicrob Agents Chemother. 1998;42:3200–3208
  69. Standring DN, Bridges EG, Placidi L, Faraj A, Loi AG, Pierra C, et al. Antiviral beta-l-nucleosides specific for hepatitis B virus infection. Antivir Chem Chemother. 2001;12:119–129
  70. Delaney WEt, Yang H, Miller MD, Gibbs CS, Xiong S. Combinations of adefovir with nucleoside analogs produce additive antiviral effects against hepatitis B virus in vitro. Antimicrob Agents Chemother. 2004;48:3702–3710
  71. Seigneres B, Martin P, Werle B, Schorr O, Jamard C, Rimsky L, et al. Effects of pyrimidine and purine analog combinations in the duck hepatitis B virus infection model. Antimicrob Agents Chemother. 2003;47:1842–1852
  72. Lai CL, Leung N, Teo EK, Tong M, Wong F, Hann HW, et al. A 1-year trial of telbivudine, lamivudine, and the combination in patients with hepatitis B e antigen-positive chronic hepatitis B. Gastroenterology. 2005;129:528–536
  73. Sung JJY, Lai J-Y, Zeuzem S, Chow WC, Heathcote EJ, Perrillo RP, et al. Lamivudine compared with lamivudine and adefovir dipivoxil for the treatment of HBeAg-positive chronic hepatitis B. J Hepatol. 2008;48:728–735
  74. Delmas J, Schorr O, Jamard C, Gibbs C, Trepo C, Hantz O, et al. Inhibitory effect of adefovir on viral DNA synthesis and covalently closed circular DNA formation in duck hepatitis B virus-infected hepatocytes in vivo and in vitro. Antimicrob Agents Chemother. 2002;46:425–433
  75. Kock J, Baumert TF, Delaney WEt, Blum HE, von Weizsacker F. Inhibitory effect of adefovir and lamivudine on the initiation of hepatitis B virus infection in primary tupaia hepatocytes. Hepatology. 2003;38:1410–1418
  76. Moraleda G, Saputelli J, Aldrich CE, Averett D, Condreay L, Mason WS. Lack of effect of antiviral therapy in nondividing hepatocyte cultures on the closed circular DNA of woodchuck hepatitis virus. J Virol. 1997;71:9392–9399
  77. Zhu Y, Yamamoto T, Cullen J, Saputelli J, Aldrich CE, Miller DS, et al. Kinetics of hepadnavirus loss from the liver during inhibition of viral DNA synthesis. J Virol. 2001;75:311–322
  78. Summers J, Mason WS. Residual integrated viral DNA after hepadnavirus clearance by nucleoside analog therapy. Proc Natl Acad Sci USA. 2004;101:638–640
  79. Yokosuka O, Omata M, Imazeki F, Okuda K, Summers J. Changes of hepatitis B virus DNA in liver and serum caused by recombinant leukocyte interferon treatment: analysis of intrahepatic replicative hepatitis B virus DNA. Hepatology. 1985;5:728–734
  80. Sung JJ, Wong ML, Bowden S, Liew CT, Hui AY, Wong VW, et al. Intrahepatic hepatitis B virus covalently closed circular DNA can be a predictor of sustained response to therapy. Gastroenterology. 2005;128:1890–1897
  81. Werle-Lapostolle B, Bowden S, Locarnini S, Wursthorn K, Petersen J, Lau G, et al. Persistence of cccDNA during the natural history of chronic hepatitis B and decline during adefovir dipivoxil therapy. Gastroenterology. 2004;126:1750–1758
  82. Maynard M, Parvaz P, Durantel S, Chevallier M, Chevallier P, Lot M, et al. Sustained HBs seroconversion during lamivudine and adefovir dipivoxil combination therapy for lamivudine failure. J Hepatol. 2005;42:279–281
  83. Lai CL, Dienstag J, Schiff E, Leung NW, Atkins M, Hunt C, et al. Prevalence and clinical correlates of YMDD variants during lamivudine therapy for patients with chronic hepatitis B. Clin Infect Dis. 2003;36:687–696
  84. Lok AS, Lai CL, Leung N, Yao GB, Cui ZY, Schiff ER, et al. Long-term safety of lamivudine treatment in patients with chronic hepatitis B. Gastroenterology. 2003;125:1714–1722
  85. van Zonneveld M, van Nunen AB, Niesters HG, de Man RA, Schalm SW, Janssen HL. Lamivudine treatment during pregnancy to prevent perinatal transmission of hepatitis B virus infection. J Viral Hepat. 2003;10:294–297
  86. Tillmann HL, Hadem J, Leifeld L, Zachou K, Canbay A, Eisenbach C, et al. Safety and efficacy of lamivudine in patients with severe acute or fulminant hepatitis B, a multicenter experience. J Viral Hepat. 2006;13:256–263
  87. Lau GK, He ML, Fong DY, Bartholomeusz A, Au WY, Lie AK, et al. Preemptive use of lamivudine reduces hepatitis B exacerbation after allogeneic hematopoietic cell transplantation. Hepatology. 2002;36:702–709
  88. Lau GK, Yiu HH, Fong DY, Cheng HC, Au WY, Lai LS, et al. Early is superior to deferred preemptive lamivudine therapy for hepatitis B patients undergoing chemotherapy. Gastroenterology. 2003;125:1742–1749
  89. Zoulim F, Poynard T, Degos F, Slama A, El Hasnaoui A, Blin P, et al. A prospective study of the evolution of lamivudine resistance mutations in patients with chronic hepatitis B treated with lamivudine. J Viral Hepat. 2006;13:278–288
  90. Perrillo R, Hann HW, Mutimer D, Willems B, Leung N, Lee WM, et al. Adefovir dipivoxil added to ongoing lamivudine in chronic hepatitis B with YMDD mutant hepatitis B virus. Gastroenterology. 2004;126:81–90
  91. Peters MG, Hann Hw H, Martin P, Heathcote EJ, Buggisch P, Rubin R, et al. Adefovir dipivoxil alone or in combination with lamivudine in patients with lamivudine-resistant chronic hepatitis B. Gastroenterology. 2004;126:91–101
  92. Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, Chang TT, Kitis G, Rizzetto M, et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B. N Engl J Med. 2003;348:800–807
  93. Marcellin P, Chang TT, Lim SG, Tong MJ, Sievert W, Shiffman ML, et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. N Engl J Med. 2003;348:808–816
  94. Durantel S, Werle B, Durantel D, Pichoud C, Currie G, Xiong S, et al. Different profiles of response to adefovir dipivoxil and factors that may influence response in patients with chronic hepatitis B. Antiviral Therapy, in press.
  95. Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, Chang TT, Kitis G, Rizzetto M, et al. Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B for up to 5 years. Gastroenterology. 2006;131:1743–1751
  96. Lampertico P, Vigano M, Manenti E, Iavarone M, Lunghi G, Colombo M. Adefovir rapidly suppresses hepatitis B in HBeAg-negative patients developing genotypic resistance to lamivudine. Hepatology. 2005;42:1414–1419
  97. Lampertico P, Marzano A, Levrero M, Santantonio T, Di Marco V, Brunetto M, et al. Adefovir and lamivudine combination therapy is superior to adefovir monotherapy for lamivudine-resistant patients with HBeAg-negative chronic hepatitis B. Hepatology. 2006;44:693A
  98. Chang TT, Gish RG, de Man R, Gadano A, Sollano J, Chao YC, et al. A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B. N Engl J Med. 2006;354:1001–1010
  99. Lai CL, Shouval D, Lok AS, Chang TT, Cheinquer H, Goodman Z, et al. Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B. N Engl J Med. 2006;354:1011–1020
  100. Colonno RJ, Rose R, Baldick CJ, Levine S, Pokornowski K, Yu CF, et al. Entecavir resistance is rare in nucleoside naive patients with hepatitis B. Hepatology. 2006;44:1656–1665
  101. Sherman M, Yurdaydin C, Sollano J, Silva M, Liaw YF, Cianciara J, et al. Entecavir for treatment of lamivudine-refractory, HBeAg-positive chronic hepatitis B. Gastroenterology. 2006;130:2039–2049
  102. Tenney DJ, Rose RE, Baldick CJ, Levine SM, Pokornowski KA, Walsh AW, et al. Two-year assessment of entecavir resistance in lamivudine-refractory hepatitis B virus patients reveals different clinical outcomes depending on the resistance substitutions present. Antimicrob Agents Chemother. 2007;51:902–911
  103. Tenney DJ, Levine SM, Rose RE, Walsh AW, Weinheimer SP, Discotto L, et al. Clinical emergence of entecavir-resistant hepatitis B virus requires additional substitutions in virus already resistant to lamivudine. Antimicrob Agents Chemother. 2004;48:3498–3507
  104. Villet S, Ollivet A, Pichoud C, Barraud L, Villeneuve JP, Trepo C, et al. Stepwise process for the development of entecavir resistance in a chronic hepatitis B virus infected patient. J Hepatol. 2007;46:531–538
  105. McMahon MA, Jilek BL, Brennan TP, Shen L, Zhou Y, Wind-Rotolo M, et al. The HBV drug entecavir – effects on HIV-1 replication and resistance. N Engl J Med. 2007;356:2614–2621
  106. Chan HL, Heathcote EJ, Marcellin P, Lai CL, Cho M, Moon YM, et al. Treatment of hepatitis B e antigen-positive chronic hepatitis with telbivudine or adefovir: a randomized trial. Ann Intern Med. 2007;147:745–754
  107. Lai CL, Gane E, Liaw YF, Hsu CW, Thongsawat S, Wang Y, et al. Telbivudine versus lamivudine in patients with chronic hepatitis B. N Engl J Med. 2007;357:2576–2588
  108. van Bommel F, Wunsche T, Mauss S, Reinke P, Bergk A, Schurmann D, et al. Comparison of adefovir and tenofovir in the treatment of lamivudine-resistant hepatitis B virus infection. Hepatology. 2004;40:1421–1425
  109. van Bommel F, Zollner B, Sarrazin C, Spengler U, Huppe D, Moller B, et al. Tenofovir for patients with lamivudine-resistant hepatitis B virus (HBV) infection and high HBV DNA level during adefovir therapy. Hepatology. 2006;44:318–325
  110. Benhamou Y, Tubiana R, Thibault V. Tenofovir disoproxil fumarate in patients with HIV and lamivudine-resistant hepatitis B virus. N Engl J Med. 2003;348:177–178
  111. Dore GJ, Cooper DA, Pozniak AL, DeJesus E, Zhong L, Miller MD, et al. Efficacy of tenofovir disoproxil fumarate in antiretroviral therapy-naive and -experienced patients coinfected with HIV-1 and hepatitis B virus. J Infect Dis. 2004;189:1185–1192
  112. Lacombe K, Gozlan J, Boelle PY, Serfaty L, Zoulim F, Valleron AJ, et al. Long-term hepatitis B virus dynamics in HIV-hepatitis B virus-co-infected patients treated with tenofovir disoproxil fumarate. Aids. 2005;19:907–915
  113. Peters MG, Andersen J, Lynch P, Liu T, Alston-Smith B, Brosgart CL, et al. Randomized controlled study of tenofovir and adefovir in chronic hepatitis B virus and HIV infection: ACTG A5127. Hepatology. 2006;44:1110–1116
  114. Marcellin P, Buti M, Krastev Z, Germanidis G, Kaita KD, Kotzev I, et al. A randomized double blind comparison of tenofovir DF (TDF) versus adefovir dipivoxil (ADV) for the treatment of HBeAg-negative chronic hepatitis B (CHB). Hepatology. 2007;46:290A
  115. Heathcote EJ, Gane E, DeMan R, Lee S, Flisiak R, Manns MP, et al. A randomized double blind comparison of tenofovir DF (TDF) versus adefovir dipivoxil (ADV) for the treatment of HBeAg-positive chronic hepatitis B (CHB). Hepatology. 2007;46:861A
  116. Locarnini S, Hatzakis A, Heathcote J, Keeffe EB, Liang TJ, Mutimer D, et al. Management of antiviral resistance in patients with chronic hepatitis B. Antivir Ther. 2004;9:679–693
  117. Di Bisceglie AM, Lai CL, Gane E, Chen Y-C, Thongsawat S, Wang Y, et al. Telbivudine globe trial: maximal early HBV suppression is predictive of optimal two-year efficacy in nucleoside-treated hepatitis B patients. Hepatology. 2006;44:230A
  118. Keeffe EB, Zeuzem S, Koff RS, Dieterich DT, Esteban-Mur R, Gane EJ, et al. Report of an international workshop: Roadmap for management of patients receiving oral therapy for chronic hepatitis B. Clin Gastroenterol Hepatol. 2007;5:890–897
  119. Lok AS, Zoulim F, Locarnini S, Bartholomeusz A, Ghany MG, Pawlotsky JM, et al. Antiviral drug-resistant HBV: standardization of nomenclature and assays and recommendations for management. Hepatology. 2007;46:254–265
  120. Nafa S, Ahmed S, Tavan D, Pichoud C, Berby F, Stuyver L, et al. Early detection of viral resistance by determination of hepatitis B virus polymerase mutations in patients treated by lamivudine for chronic hepatitis B. Hepatology. 2000;32:1078–1088
  121. Allen MI, Deslauriers M, Andrews CW, Tipples GA, Walters KA, Tyrrell DL, et al. Identification and characterization of mutations in hepatitis B virus resistant to lamivudine. Lamivudine clinical investigation group. Hepatology. 1998;27:1670–1677
  122. Yang H, Qi X, Sabogal A, Miller M, Xiong S, Delaney WEt. Cross-resistance testing of next-generation nucleoside and nucleotide analogues against lamivudine-resistant HBV. Antivir Ther. 2005;10:625–633
  123. Angus P, Vaughan R, Xiong S, Yang H, Delaney W, Gibbs C, et al. Resistance to adefovir dipivoxil therapy associated with the selection of a novel mutation in the HBV polymerase. Gastroenterology. 2003;125:292–297
  124. Villeneuve JP, Durantel D, Durantel S, Westland C, Xiong S, Brosgart CL, et al. Selection of a hepatitis B virus strain resistant to adefovir in a liver transplantation patient. J Hepatol. 2003;39:1085–1089
  125. Villet S, Pichoud C, Villeneuve JP, Trepo C, Zoulim F. Selection of a multiple drug-resistant hepatitis B virus strain in a liver-transplanted patient. Gastroenterology. 2006;131:1253–1261
  126. Qi X, Xiong S, Yang H, Miller M, Delaney WEt. In vitro susceptibility of adefovir-associated hepatitis B virus polymerase mutations to other antiviral agents. Antivir Ther. 2007;12:355–362
  127. Schildgen O, Sirma H, Funk A, Olotu C, Wend UC, Hartmann H, et al. Variant of hepatitis B virus with primary resistance to adefovir. N Engl J Med. 2006;354:1807–1812
  128. Curtis M, Zhu Y, Borroto-Esoda K. Hepatitis B virus containing the I233V mutation in the polymerase reverse-transcriptase domain remains sensitive to inhibition by adefovir. J Infect Dis. 2007;196:1483–1486
  129. Sheldon J, Camino N, Rodes B, Bartholomeusz A, Kuiper M, Tacke F, et al. Selection of hepatitis B virus polymerase mutations in HIV-coinfected patients treated with tenofovir. Antivir Ther. 2005;10:727–734
  130. Yim HJ, Hussain M, Liu Y, Wong SN, Fung SK, Lok AS. Evolution of multi-drug resistant hepatitis B virus during sequential therapy. Hepatology. 2006;44:703–712
  131. Brunelle MN, Jacquard AC, Pichoud C, Durantel D, Carrouee-Durantel S, Villeneuve JP, et al. Susceptibility to antivirals of a human HBV strain with mutations conferring resistance to both lamivudine and adefovir. Hepatology. 2005;41:1391–1398
  132. Lampertico P, Vigano M, Manenti E, Iavarone M, Sablon E, Colombo M. Low resistance to adefovir combined with lamivudine: a 3-year study of 145 lamivudine-resistant hepatitis B patients. Gastroenterology. 2007;133:1445–1451
  133. Zoulim F. Antiviral therapy of chronic hepatitis B. Antiviral Res. 2006;71:206–215
  134. Yuen MF, Fong DY, Wong DK, Yuen JC, Fung J, Lai CL. Hepatitis B virus DNA levels at week 4 of lamivudine treatment predict the 5-year ideal response. Hepatology. 2007;46:1695–1703
  135. Stuyver L, Van Geyt C, De Gendt S, Van Reybroeck G, Zoulim F, Leroux-Roels G, et al. Line probe assay for monitoring drug resistance in hepatitis B virus-infected patients during antiviral therapy. J Clin Microbiol. 2000;38:702–707
  136. Clavel F, Hance AJ. HIV drug resistance. N Engl J Med. 2004;350:1023–1035
  137. Hui C-K, Zhang H-Y, Bowden S, Locarnini S, Luk JM, Leung K-W, et al. 96 weeks combination of adefovir dipivoxil plus emtricitabine vs. adefovir dipivoxil monotherapy in the treatment of chronic hepatitis B. J Hepatol. 2008;48:714–720
  138. Litwin S, Toll E, Jilbert AR, Mason WS. The competing roles of virus replication and hepatocyte death rates in the emergence of drug-resistant mutants: theoretical considerations. J Clin Virol. 2005;34:S96–S107
  139. Brunelle MN, Lucifora J, Neyts J, Villet S, Holy A, Trepo C, et al. In vitro activity of 2,4-diamino-6-[2-(phosphonomethoxy)ethoxy]-pyrimidine against multidrug-resistant hepatitis B virus mutants. Antimicrob Agents Chemother. 2007;51:2240–2243

 F. Zoulim declares that he is a consultant for: Gilead Sciences, Bristol Myers Squibb and Novartis. R.P. Perrillo declares that he receives funding from Novartis and Bristol Myers Squibb for clinical research in hepatitis B. This study was not funded by any of the above.

PII: S0168-8278(08)00057-3

doi: 10.1016/j.jhep.2008.01.011

Journal of Hepatology
Volume 48 , Pages S2-S19 , 2008